The activation of protooncogenes is a general mechanism of carcinogenesis. Induction of breast cancer in mice by the retrovirus, mouse mammary tumor virus (MMTV), results from proviral insertion in the vicinity of one of a series of protooncogenes (the int-x, or wnt-x series) and activation of these genes uniquely in mammary cells. A tissue-specific enhancer was previously discovered at the 5' end of the long terminal repeat. We have mapped this enhancer to a 100bp sequence and identified four activities acting on this sequence: mp4, mp5, F3 and F12. The mp5 protein is apparently related to AP2, a previously described transcription factor. This activity is completely absent in some cell types, such as liver cells (HepG2). The MMTV enhancer mp5 site can be complemented in HepG2 cells by expression of human AP2. Thus, tissue-specific protooncogene activation in murine breast cancer is mediated, in part, through the recruitment of cell-specific factors by the activating provirus. The activities that interact with this locus are also present and active in human breast cancer cells, arguing that this mechanism of tissue-specific expression is conserved across the murine and human species.